CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies

J Clin Pharmacol. 2013 Aug;53(8):866-77. doi: 10.1002/jcph.116. Epub 2013 Jun 10.


Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells. This study evaluated the CYP3A-mediated drug-drug interaction potential of brentuximab vedotin and the excretion of MMAE. Two 21-day cycles of brentuximab vedotin (1.2 or 1.8 mg/kg intravenously) were administered to 56 patients with CD30-positive hematologic malignancies. Each patient also received either a sensitive CYP3A substrate (midazolam), an effective inducer (rifampin), or a strong inhibitor (ketoconazole). Brentuximab vedotin did not affect midazolam exposures. ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, MMAE exposures were lower with rifampin and higher with ketoconazole. The short-term safety profile of brentuximab vedotin in this study was generally consistent with historic clinical observations. The most common adverse events were nausea, fatigue, diarrhea, headache, pyrexia, and neutropenia. Over a 1-week period, ∼23.5% of intact MMAE was recovered after administration of brentuximab vedotin; all other species were below the limit of quantitation. The primary excretion route is via feces (median 72% of the recovered MMAE). These results suggest that brentuximab vedotin (1.8 mg/kg) and MMAE are neither inhibitors nor inducers of CYP3A; however, MMAE is a substrate of CYP3A.

Trial registration: NCT01026415.

Keywords: biotechnology; clinical pharmacology; clinical trials; drug metabolism; oncology; pharmacokinetics.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Brentuximab Vedotin
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors
  • Drug Interactions
  • Feces / chemistry
  • Female
  • Hematologic Neoplasms / metabolism*
  • Humans
  • Immunoconjugates / administration & dosage
  • Immunoconjugates / adverse effects
  • Immunoconjugates / pharmacokinetics*
  • Ketoconazole / administration & dosage
  • Ketoconazole / adverse effects
  • Ki-1 Antigen / immunology*
  • Male
  • Midazolam / administration & dosage
  • Midazolam / adverse effects
  • Midazolam / pharmacokinetics
  • Middle Aged
  • Oligopeptides / metabolism*
  • Rifampin / administration & dosage
  • Rifampin / adverse effects
  • Young Adult


  • Antineoplastic Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Immunoconjugates
  • Ki-1 Antigen
  • Oligopeptides
  • Brentuximab Vedotin
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • Midazolam
  • Ketoconazole
  • monomethyl auristatin E
  • Rifampin

Associated data